Debilitation, i.e. loss of weight, strength, vascular weakness, and other symptoms are natural sequelae of many diseases which afflict humans. These may include, for example bacterial infections such as tuberculosis; viral infections, particularly retroviral infections including HIV infections such as AIDS; various forms of arthritis particularly rheumatoid and degenerative; ulcerative colitis; regional enteritis; and the like. Human patients with these symptoms may present with an acute condition such as septic shock or with a chronic condition such as cachexia.
U.S. Pat. No. 2,830,991 describes a class of therapeutic agents of the general formula I ##STR4## wherein R is selected from the group consisting of hydrogen, alkyl radicals containing 1-6 carbon atoms, the phenyl radical, and the benzyl radical; and wherein R' is selected from the group consisting of the phthalimido radical and the succinimido radical.
The subject matter of this patent and of any other patents or publications identified in this disclosure are incorporated herein by reference.
Preferred compounds within the scope of the above formula I, for use in this invention are:
3-phthalimido-2,6-dioxo-1-ethyl piperidine PA1 3-phthalimido-2,6-dioxo-1-phenyl piperidine PA1 3-phthalimido-2,6-dioxo-1-benzyl piperidine PA1 3-phthalimido-2,6-dioxo-1-allyl piperidine PA1 3-phthalimido-2,6-dioxo-piperidine
As described in the patent, the compounds are produced by reacting an aliphatic dicarboxylic acid, which contains five carbon atoms in a straight chain, the methylene groups of which are substituted by the substituents in accordance with the appropriate general formula, with urea or substitution products thereof or with a primary amine or an acid amide in such manner that water is split off and the ring is closed. If an amino group is present in the aliphatic chain, this group must not exist in free form in this stage of the process, since otherwise there is the danger of this amino group participating in an undesirable manner in the reaction. Instead of using the dicarboxylic acid, it is also possible to employ functional derivatives thereof, such as acid halides, acid esters and acid amides.
Compounds of the glutaminic acid series may be used as starting materials for the present invention. In this case also, the acid halides, esters and amides of glutaminic acid may be employed instead of the acid itself. It is known that glutaminic acids tends to form 5-membered rings with a free amino group. This reaction is undesirable for the purposes of the present invention. The amino group must therefore be substituted or protected prior to the ring-closing reaction. The protection of the amino group may be carried out, when using products of the glutaminic acid series, by introducing the phthalyl, succinyl or like radical in a manner known per se. The proportions of the components used for the ring formation must be such that at least 1 mol of the compound yielding the imide nitrogen is used to one mol of the glutaminic acid component.
The first compound listed above is prepared by reacting 27.7 g. of N-phthalyl glutaminic acid with 66 g. of a 33% solution of ethyl amine in water and slowly heating in an oil bath 160.degree.-180.degree. C., the mixture being maintained at this temperature for 15 to 20 minutes. The reaction product is recrystallised from alcohol by fractionation. It melts at 209.degree. C.
The last compound listed above prepared by reacting 13 g. of phthalyl glutaminic acid anhydride and 6 g. of urea in 75 cc. of absolute xylene for 4 hours at the boiling point of the mixture. Formation of a sublimate takes place with evolution of ammonia and carbon dioxide. The xylene is then distilled off in vacuo and the residue recrystallized from 95% alcohol by fractionation. In addition to some phthalimide and phthalyl glutamine, the required N.sub.2 -phthalyl glutaminic acid imide is obtained, having a melting point of 269.degree.-271.degree. C.
In the patent, the compounds are disclosed as having low toxicity and as useful for certain spasmolytic and antihistaminic effects. The compound 3-phthalimido-2,6-dioxopiperidine is disclosed as being particularly useful as a sedative. This compound was marketed as a sedative under the generic name thalidomide. It was subsequently discovered to be teratogenic and was withdrawn from the market.
Despite its teratogenicity, thalidomide has long been employed for the treatment of erythema nodosum leprosum (ENL) an accute inflammatory state occurring in lepromatous leprosy. See, for example Mellin, G. W., and M. Katzenstein. N. Engl. J. Med. 267:1184 (1962). More recently, it has been shown to be useful in the treatment of graft-versus-host disease by Vogelsany, G. B., S. Taylor, G. Gordon and A. D. Hess. Transplant Proc. 23:904 (1986); for treatment of reheumatoid arthritis by O. Gutierrez-Rodriguez, P. Starusta-Bacai and O. Gutierrez-Montes. The Journal of Rheumatology 16:2 158 (1989); and for treatment of aphthous ulceration in patients positive for HIV antibody. Brit. Med. J. 298:432 (1989).
The tumor necrosis factor (TNF-.sub..alpha.) is one of several cytokines released mainly by mononulear phagocytes together with several other cytokines in response to stimuli to the immune system. It is required for a cell mediated immune response to overcome infections. As its name suggests, it is associated with the destruction of tumor cells. It is not present in measureable amounts in normal sera, but appears, often very rapidly, in response to immunostimulators such as bacterial and viral infections, particularly HIV infections. In the case of chronic infection it may be found in the sera at relatively high or low levels for extended periods of time. It may also appear suddenly in high concentrations in response to release of a toxin by an invading bacteria. It is markedly elevated in ENL.
TNF-.sub..alpha. has been recognized as manifesting a dose dependent toxicity. If present at low levels for too long a period it results in cachexia. At high levels even for a short time it results in septic shock.
Cachexia is a general weight loss and wasting occurring in the course of a chronic disease. More specifically, it is a weight loss not accounted for by decreased caloric intake. It is associated with cancer, the opportunistic infections of AIDS, inflammatory diseases, parasitic diseases, tuberculosis, high dose IL-2 therapy and the like. It is a chronic condition related to chronic diseases.
Septic shock is an acute condition usually, but not always attributed to infection or to toxic substances in the tissue. It is characterized by hypotension due to loss of vascular tone. It may result in patient collapse, or even death if not treated promptly and efficiently.
The retroviruses are a broad group of RNA viruses which, during their replication, employ the reverse transcription enzyme (RT) to convert a RNA message to DNA. The retroviridae family of viruses includes lentiviruses (visna, maedi, progressive pneumonia virus -"slow viruses"), spumaviruses (foamy viruses) and oncornaviruses (types A, B, C, D, RNA tumor viruses). The retroviruses have been shown to infect murine, avian, feline, primate, and human species.
The human immunodeficiency virus (HIV-1) or human T-Cell lymphotropic viruse (HTLV-III) which causes Acquired Immune Deficiency Syndrome (AIDS), AIDS related complex (ARC) and other AIDS related diseases is a retrovirus. TNF-.sub..alpha. functions in an autocrine manner in the induction of HIV-1 expression (G. Poli et al, PNAs Vol 87 p 782, 1990).
It is apparent, therefore, that it is necessary to control the concentration of TNF-.sub..alpha. in the sera to avoid the debilitating effects of abnormal concentrations of this cytokine including, for example, cachexia and septic shock.
Other cytokines which are necessary for a proper immune response are also produced by mononuclear phagocytes. These include, for example, various interleukins such as IL-1, IL-6, IL-8 and the granulocyte macrophage colony stimulating factor, GM-CSF. Still other cytokines are produced by the T-cells. It is desirable to control the concentration of TNF without appreciably affecting the concentration and activity of other cytokines.
Heretofore, antiinflammatory and immunosuppresive steroids such as prednisolone and dexamethasone have been employed to treat the debilitating effects of TNF-.sub..alpha.. Unfortunately, these therapeutic agents also block the production of other cytokines so that the patients become susceptible to life threatening infections.